title: Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells.
abstract: A central role for the mammalian target of rapamycin (mTOR) in innate immunity has been recently defined by its ability to limit proinflammatory mediators. Although glucocorticoids (GCs) exert potent anti-inflammatory effects in innate immune cells, it is currently unknown whether the mTOR pathway interferes with GC signaling. Here we show that inhibition of mTOR with rapamycin or Torin1 prevented the anti-inflammatory potency of GC both in human monocytes and myeloid dendritic cells. GCs could not suppress nuclear factor-κB and JNK activation, the expression of proinflammatory cytokines, and the promotion of Th1 responses when mTOR was inhibited. Interestingly, long-term activation of monocytes with lipopolysaccharide enhanced the expression of TSC2, the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished mTOR activation. Renal transplant patients receiving rapamycin but not those receiving calcineurin inhibitors displayed a state of innate immune cell hyper-responsiveness despite the concurrent use of GC. Finally, mTOR inhibition was able to override the healing phenotype of dexamethasone in a murine lipopolysaccharide shock model. Collectively, these data identify a novel link between the glucocorticoid receptor and mTOR in innate immune cells, which is of considerable clinical importance in a variety of disorders, including allogeneic transplantation, autoimmune diseases, and cancer.
authors.affiliation: Department of Internal Medicine III, Division of Nephrology & Dialysis, Medical University Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weichhart
authors.forename: Michael
authors.initials: M
authors.lastname: Haidinger
authors.forename: Karl
authors.initials: K
authors.lastname: Katholnig
authors.forename: Chantal
authors.initials: C
authors.lastname: Kopecky
authors.forename: Marko
authors.initials: M
authors.lastname: Poglitsch
authors.forename: Caroline
authors.initials: C
authors.lastname: Lassnig
authors.forename: Margit
authors.initials: M
authors.lastname: Rosner
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Zlabinger
authors.forename: Markus
authors.initials: M
authors.lastname: Hengstschläger
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Walter H
authors.initials: WH
authors.lastname: Hörl
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Säemann
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000276:immunology
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D009287:Naphthyridines; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus